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Handbook of Clinical Neurology, Vol. 145 (3rd series)
Neuropathology
G.G. Kovacs and I. Alafuzoff, Editors
http://dx.doi.org/10.1016/B978-0-12-802395-2.00019-5
Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 19

Inflammatory demyelinating diseases of the central

nervous system
€
ROMANA HOFTBERGER 1
AND HANS LASSMANN2*
1
Institute of Neurology, Medical University of Vienna, Vienna, Austria
2
Center for Brain Research, Medical University of Vienna, Vienna, Austria

Abstract
Inflammatory demyelinating diseases are a heterogeneous group of disorders, which occur against the
background of an acute or chronic inflammatory process. The pathologic hallmark of multiple sclerosis
(MS) is the presence of focal demyelinated lesions with partial axonal preservation and reactive astroglio-
sis. Demyelinated plaques are present in the white as well as gray matter, such as the cerebral or cerebellar
cortex and brainstem nuclei. Activity of the disease process is reflected by the presence of lesions with
ongoing myelin destruction. Axonal and neuronal destruction in the lesions is a major substrate for per-
manent neurologic deficit in MS patients. The MS pathology is qualitatively similar in different disease
stages, such as relapsing remitting MS or secondary or primary progressive MS, but the prevalence of
different lesion types differs quantitatively. Acute MS and Balo’s type of concentric sclerosis appear to
be variants of classic MS. In contrast, neuromyelitis optica (NMO) and spectrum disorders (NMOSD)
are inflammatory diseases with primary injury of astrocytes, mediated by aquaporin-4 antibodies. Finally,
we discuss the histopathology of other inflammatory demyelinating diseases such as acute disseminated
encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated demyelination. Knowl-
edge of the heterogenous immunopathology in demyelinating diseases is important, to understand the clin-
ical presentation and disease course and to find the optimal treatment for an individual patient.

associated with a specific spectrum of demyelinating dis-

INTRODUCTION
Historically the first description of multiple sclerosis
(MS) as a neuropathologic entity dates from 1868 by
Charcot; subsequently, less prevalent disorders such as
neuromyelitis optica (NMO) (Devic, 1894), Marburg
type of MS (Marburg, 1906), or concentric sclerosis of
Balo (1928) were demonstrated and considered as sub-
types of MS. With the availability of immunohistochem-
ical markers it became apparent that there is a
considerable pathologic distinction between these disor-
ders and the morphologic patterns were associated with
different mechanisms of demyelination (Lucchinetti
et al., 2000, 2002). This observation was further sup-
ported by the discovery of autoantibodies that are
eases. Anti-aquaporin-4 antibodies (AQP4-abs) are asso-
ciated with NMO and limited forms of the disease, such
as isolated optic neuritis or myelitis, which are now sub-
sumed under the term NMO spectrum disorders
(NMOSD). Meanwhile, the use of AQP4-abs as bio-
marker for NMOSD is well established and has major
prognostic and therapeutic implications. Anti-myelin oli-
godendrocyte glycoprotein (MOG) antibodies are found
in patients with acute dissemimated encephalomyelitis
(ADEM), NMOSD, and, rarely, MS-like clinical presen-
tation (Lennon et al., 2004; Kim et al., 2015; Wingerchuk
et al., 2015; Sepulveda et al., 2016), but they may define
a unique and specific variant of inflammatory demyelin-
ating diseases. It is quite probable that, even within the

*Correspondence to: Hans Lassmann, MD, Center for Brain Research, Medical University of Vienna, Spitalgasse, 1090 Vienna,
Austria. E-mail: hans.lassmann@meduniwien.ac.at
264 €
R. HOFTBERGER AND H. LASSMANN
classic spectrum of MS, variabilities may represent dif-
ferent disease processes or perhaps different triggering
factors and will classify future distinct entities.
MULTIPLE SCLEROSIS
Clinical and diagnostic features
The clinical diagnosis of MS is based on the demonstra-
tion of demyelinating lesions disseminated in time and
space. In addition to the neurologic symptoms, the find-
ing of magnetic resonance imaging (MRI) lesions consis-
tent with MS (Barkhof et al., 1997; Tintore et al., 2000),
demonstration of oligoclonal bands in cerebrospinal
fluid (CSF) (Link and Tibbling, 1977), and/or detection
of abnormal visual evoked potentials (delay with a well-
preserved wave form) are recommended to provide a cor-
rect diagnosis (McDonald et al., 2001). Patients with MS
may present a monosymptomatic disease suggestive of
MS (clinically isolated syndrome), a classic relapsing
remitting course, or a primary or secondary progressive
disease. Disease progression is defined as continuous
deterioration of neurologic symptoms despite only a
few new MRI lesions and a rare incidence of contrast-
enhancing lesions. The majority of patients with MS start
with a relapsing remitting MS, which later converts into a
secondary progressive disease. In primary progressive
MS the disease starts with continuous progression from
its onset. The pathogenetic mechanism underlying pro-
gression is supposed to result at least in part from an
ongoing inflammatory reaction behind a closed blood–
brain barrier (BBB).
Pathologic features of classic MS
The histopathologic hallmark of MS is the formation of
inflammatory demyelinating lesions with variable axo-
nal damage and astrocytic gliosis.
INFLAMMATION
Blood–brain barrier
In the pathogenesis of MS plaques it is currently sup-
posed that autoreactive, myelin-specific lymphocytes
are activated outside the central nervous system
(CNS), cross the BBB, and form new inflammatory
demyelinating lesions (Ciccarelli et al., 2014). The cross-
ing of the BBB is dependent on the interaction of integ-
rins on the surface of lymphocytes with cell adhesion
molecules on endothelial cells (Takeshita and
Ransohoff, 2012). One of the most important interactions
is the binding of the very late antigen-4 integrin on lym-
phocytes to vascular cell adhesion molecule-1 on brain
vascular endothelium (Takeshita and Ransohoff, 2012),
which can be therapeutically blocked by the monoclonal
antibody natalizumab in relapsing remitting MS (Polman
et al., 2006).
The high efficacy of natalizumab treatment is due to
its blockade of the migration of many different inflam-
matory cell types. However, it has been suggested that
different inflammatory cell types use different entry path-
ways, by using distinctly different adhesion molecule
interactions or chemokines such as a4integrin, ICAM,
ALCAM, CCL5, CXCL10, and CCL2/CCR2 by Th1+,
Th17+ and CD8+ T cells (Engelhardt and Ransohoff,
2005; Cayrol et al., 2008; Ifergan et al., 2011) or
CXCL12/CXCR4, CCR7/CCL19/TLR4 by monocytes
(Man et al., 2012; Paradis et al., 2016). When these obser-
vations are confirmed and validated in different human
diseases, including MS, more specific blockade of the
migration of those leukocytes, which are most relevant
in driving disease and tissue damage, may lead to effec-
tive therapies with fewer side-effects, compared to those
currently available.
Morphologically, the disturbance of BBB permeabil-
ity can be visualized with ultrastructural investigation
and immunohistochemistry. By ultrastructure, endothe-
lial cells show an increase in pinocytic vesicles in active
MS lesions (Brown, 1978) and by immunohistochemis-
try, a perivascular leakage of serum proteins and, more
specifically, an expression of molecular markers for
leaky endothelial cells is seen (Kirk et al., 2003;
Hochmeister et al., 2006). In MRI studies, the BBB per-
meability is visualized with contrast enhancement. The
dynamic changes from nodular enhancement during
early lesion formation to a ring-enhancing lesion in a
later stage suggest that BBB leakage initally starts in
the inflamed central vein and later mainly occurs at the
active margin (Gaitan et al., 2011). It is important to note
that contrast enhancement in MRI depicts BBB leakage,
but is not a direct marker of inflammation. In particular,
in patients with progressive MS, widespread and pro-
found inflammation is seen in the brain, which takes
place in part behind a closed or repaired BBB
(Hochmeister et al., 2006).
T lymphocytes
Neuropathologic tissue examination recognizes peri-
vascular cell cuffs and meningeal inflammatory infil-
trates composed of CD3 + and CD8 + T cells, while
CD4 + T cells, CD20-positive B cells, and plasma cells
are present in variable and lower numbers (Frischer
et al., 2009). Lymphocytic inflammation is associated
with profound macrophage infiltration and microglia
activation, in particular in lesions with active demyelin-
ation or tissue injury. Neutrophils and eosinophils are
usually not observed but more characteristic for lesions
in NMO. In the parenchyma of MS plaques the
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM
inflammatory infiltrates are dominated by CD8 + T cells
(Friese and Fugger, 2005) and show a clonal expansion
that persists over time (Babbe et al., 2000). In some cases
large numbers of cytotoxic T cells were identified in
close contact with oligodendrocytes or axons and
showed a polarization of granzyme B towards the site
of contact (Neumann et al., 2002). For these reasons it
has been hypothesized that cytotoxic T cells may in part
selectively mediate the inflammatory demyelination in
MS and this view is supported by experimental models
of brain inflammation induced by oligodendrocyte-
reactive CD8 + T cells, which unequivocally show pri-
mary demyelination (Saxena et al., 2008). However, it
turned out to be very difficult to induce demyelination
by passive transfer of CD8 + T cells in animal models
(Huseby et al., 2001; Na et al., 2008; Saxena et al.,
2008). This was partly explained by an antigen-specific
clonal deletion of cytotoxic T cells by oligodendrocytes
in the intact CNS (Na et al., 2012), and this effect
could be abolished with an immunologic priming of
the CNS by an infectious process (Na et al., 2012).
An alternative theory suggests that at least a subpopu-
lation of T cells may play a neuroprotective rather than a
destructive role (Stadelmann et al., 2005). This is
supported also by the detection of HLA-E on endo-
thelial cells and astrocytes in active MS lesions that
induce an immunoregulatory phenotype in CD8 + cells
(Durrenberger et al., 2012). Interestingly, lower num-
bers of circulating regulatory T cells (FoxP3+, CD8+)
in the circulation of relapsing MS patients compared to
those in remission were detected and held responsible
for the ongoing autoimmune attack in the MS lesion
(Boppana et al., 2011), but the numbers of FoxP3+
T cells within MS lesions is very low (Fritzsching
et al., 2011).
The CD4 + T cells are present in variable amounts in
perivascular and meningeal inflammatory infiltrates,
but their number overall is small and clonal expansion
is rare in comparison to CD8 + cells (Babbe et al., 2000).
It is believed that helper T cells initiate the formation of
MS lesions by recruitment of macrophages that subse-
quently present antigens. The antigen that drives the
autoimmune process however is unknown and it is
supposed that the antigenic epitope repertoire may
increase and change over time (called epitope spread-
ing) (Davies et al., 2005). The theory that CD4 + helper
T cells are responsible for the formation of new demy-
elinating lesions is supported by animal models of
experimental autoimmune encephalomyelitis (EAE)
that are mainly induced by CD4 + T-cell-driven inflam-
mation (Billiau and Matthys, 2001). However, MS ther-
apies that selectively target CD4 + T-cell response were
shown to be ineffective (van Oosten et al., 1997; Segal
et al., 2008).
265
B lymphocytes
B cells are sparse in the parenchyma of MS lesions in
comparison to T cells (Frischer et al., 2009). B cells
and plasma cells can mainly be found in the perivascular
and meningeal inflammatory infiltrates. In patients with
pronounced inflammatory pathology, large B-cell aggre-
gates may occur and show features of tertiary lymphoid
follicles with germinal center-like structural organization
(Serafini et al., 2004; Aloisi and Pujol-Borrell, 2006;
Magliozzi et al., 2007). It has been shown that meningeal
inflammation correlates with the extent of active demy-
elination and neurodegeneration in the underlying cortex
(see later under demyelinating lesions in the gray matter)
(Magliozzi et al., 2010; Howell et al., 2011; Fischer et al.,
2013). B cells mature to plasma cells that produce immu-
noglobulins that are mainly IgG1 and IgG3 isotypes and,
less frequently, IgA and IgM isotypes. Lipid-specific
IgM in the CSF has been documented in patients with
MS and may reflect a negative prognostic marker
(Thangarajh et al., 2008). Ig-producing B cells undergo
antigen-specific clonal expansion, which is supported by
prominent somatic hypermutation of Ig chains within the
CSF and brain lesions of MS patients (Obermeier et al.,
2011; Beltran et al., 2014). Although the exact role of
B lymphocytes in the formation of MS lesions is still
unclear, some patients show good response to therapies,
which target T- and B-cell infiltration into the CNS
(alemtuzumab) (Thompson et al., 2010) or which selec-
tively eliminate circulating B cells (rituximab, ocrelizu-
mab) (Hauser et al., 2008, 2017; Montalban et al., 2017).
Microglia and macrophages
The number of macrophages within MS lesions depends
on the stage of activity. Actively demyelinating plaques
contain high numbers of lipid-laden macrophages
throughout the lesion, chronically active plaques are
delineated by a rim of macrophages and activated micro-
glia, while the lesion center is devoid of macrophages,
and chronically inactive plaques contain hardly any mac-
rophages (Kuhlmann et al., 2017). The role of microglia
and macrophages in the pathogenesis of MS plaques has
been extensively studied during the last decades. Origi-
nally they were mainly seen as proinflammatory cells
exacerbating tissue damage by antigen presentation via
major histocompatibility complex (MHC) molecules,
production of oxygen and nitric oxide radicals, secretion
of proinflammatory cytokines, and phagocytosis. Macro-
phages were used as parameters in the time staging of MS
lesions based on the presence of partly digested myelin
components within their cytoplasm (Bruck et al.,
1995). In vitro MOG and myelin-associated glycoprotein
(MAG) are degraded after 1 day (Fig. 19.1A), while the
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R. HOFTBERGER AND H. LASSMANN

Fig. 19.1. Time course of myelin degradation in multiple sclerosis. Minor myelin proteins such as myelin oligodendrocyte gly-
coprotein (MOG) are degraded within 1–2 days of phagocytosis (A, arrows: MOG-positive myelin debris within macrophages),
while major myelin proteins such as myelin basic protein (MBP) may persist for up to 6 days (B, arrows: MBP-positive myelin
debris within macrophages). In later stages, macrophages contain periodic acid–Schiff (PAS)-positive residual glycoproteins
(C, arrows: PAS-positive macrophages) and lipids (D, arrows: foamy and vacuolated macrophages).  600.

degradation of proteolipid protein (PLP) and myelin
basic protein is much slower following myelin phagocy-
tosis (Fig. 19.1B) (van der Goes et al., 2005).
Immunohistochemical staining for these myelin pro-
teins can give an indication of the time interval between
actual myelin destruction and analysis of the tissue
(Bruck et al., 1995). In later stages, residual glycopro-
teins in macrophage lysosomes can be stained with peri-
odic acid–Schiff (Fig. 19.1 C and D). Later it became
clear that macrophages may also be involved in remye-
lination and neuroprotection and their maturation into
an anti-inflammatory M2 phenotype occurs after they
have ingested myelin (Boven et al., 2006). So far, how-
ever, a clear lesion stage-dependent macrophage polari-
zation has not become apparent; most macrophages and
microglia showed a phenotype, which is intermediate
between M1 and M2 cells (Vogel et al., 2013).
DEMYELINATION
Myelin sheath
Myelin sheaths are formed and maintained by oligoden-
drocytes (Dhaunchak and Nave, 2007). Myelin assembly
and long-term preservation require a number of proteins
that are either expressed in the myelin or at the axonal
membrane. MOG is localized on the outermost surface
of the myelin sheath. The protein belongs to the immu-
noglobulin superfamily and might serve as cell adhesion
molecule, a regulator of microtubule stability, and a
mediator of interactions between myelin and the immune
system (Johns and Bernard, 1999). Structural myelin
proteins such as proteolipid protein and myelin basic pro-
tein are necessary for exact membrane-to-membrane
spacing, whereas 2’3’-cyclic nucleotide 3’phosphodies-
terase (CNP) and MAG are expressed at the periphery of
the oligodendrocytes and the latter plays a role in linking
the innermost periaxonal loop of oligodendrocytes
with the axon (Lappe-Siefke et al., 2003). At the node
of Ranvier axoglial proteins like contactin1 and
neurofascin155/186 form glioaxonal junctions to keep
sodium channels in the nodal region, which is critical
for the efficient saltatory conduction of the action poten-
tial (Sherman et al., 2005).
Mechanisms of demyelination
Demyelination is the common final phase in the pathol-
ogy of MS and comprises the stripping of myelin lamel-
lae and removal of myelin fragments by phagocytes.
There is evidence that demyelination is driven by differ-
ent mechanisms involving the adaptive and innate
immune system (Lucchinetti et al., 2000). Diffusible
oxygen, nitric oxide, and nitrogen species, mainly pro-
duced by macrophages and activated microglia, are the
key mechanisms for myelin and oligodendrocyte damage
during early demyelination (Hill et al., 2004; Haider
et al., 2011). In a subgroup of patients (pattern 1) this rel-
atively indiscriminate damage is probably a major mech-
anism of injury. In about 50% of patients with short and
aggressive disease course an additional deposition of
immunoglobulins and complement was shown within
the lesions, suggesting an antibody-mediated process
(pattern 2). First evidence for a direct antibody–antigen
interaction was gained in EAE models that were induced
by encephalitogenic T cells and modified by monoclonal
antibodies against MOG (Schluesener et al., 1987;
Linington et al., 1988). Later, autoantibodies to the astro-
cytic waterchannel AQP4 were discovered and are now
sensitive and specific diagnostic markers for NMOSD.
Indirect evidence for antibody-mediated damage
was found in patients with IgM antibody deposition on
myelin and demyelinated axons that colocalized with
complement C3b next to antibody–antigen immuncom-
plexes in macrophages (Sadaba et al., 2012). In another
distinct group of patients, oxidative stress may cause an
oligodendrogliopathy that starts in the distal processes of
oligodendrocytes with preferential loss of MAG and later
results in apoptosis of the oligodendrocyte (pattern 3).
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM
Since preferential MAG loss is a prominent feature of
early white-matter stroke and some types of viral enceph-
alitis, and HIF1alpha, a marker for hypoxia, is strongly
expressed in these lesions, it has been hypothesized that
the “dying-back” oligodendrogliopathy may result from
a hypoxia-like tissue injury. This may be induced by dis-
turbance of microcirculation or impairment of mitochon-
drial energy metabolism as a result of reactive oxygen
species produced by macrophages (Aboul-Enein et al.,
2003; Mahad et al., 2008). Finally, very few cases have
been identified with apoptotic oligodendrocytes in the
normal-appearing white matter (NAWM), which sug-
gests a primary oligodendrogliopathy in these patients
(pattern 4). However, more cases are needed to elucidate
the underlying pathogenetic mechanisms.
Neuropathology of MS plaques
MS lesions can arise at any site in the CNS (Figs 19.2 and
19.3); however, there is a predilection for areas with high
venous density, related to the fact that veins are the prime
sites for the egress of inflammatory cells through the
blood to the brain (Waksman, 1960). In progressive
MS, lesions in addition accumulate in watershed areas
with low arterial blood supply, such as the periventricular
white matter (Haider et al., 2016). This has been attrib-
uted to an amplification of oxidative injury and histo-
toxic hypoxia in areas of reduced arterial perfusion and
oxygen supply. The demyelinated lesions are typically
well demarcated and centered by an inflamed vein.
267
Finger-like protrusions may occur along inflamed veins
and are called Dawson fingers.
Classic active lesions. Actively demyelinating lesions
are mainly found in biopsy specimens or in autopsy tis-
sue of patients who died early after disease onset
(Fig. 19.4) (Frischer et al., 2015). Active lesions are char-
acterized by numerous macrophages with early myelin
degradation products within their cytoplasm and expres-
sion of the early macrophage marker MRP14 (Fig. 19.4
A and B). Moreover a considerable number of T cells and
a variable number of perivascular and meningeal B cells
and plasma cells are visible (Fig. 19.4 C–F). Within the
lesions remaining oligodendrocytes show signs of acti-
vation with large, round nuclei and broadened cyto-
plasm, which may reflect early remyelination
(Goldschmidt et al., 2009; Hoftberger et al., 2010). When
the entire lesion is filled with myelin-containing macro-
phages, such a lesion is called acute plaque. Chronic
active lesions are present, when myelin-containing mac-
rophages are densely packed at the edge of a lesion with
an inactive core. Acute axonal damage with amyloid pre-
cursor protein-positive spheroids is abundant within
active plaques (Kuhlmann et al., 2002). The astrocytes
are strongly activated with enlarged cytoplasm and often
bizarre or multiple nuclei (so-called Creutzfeldt cells)
and form a protoplasmic gliosis. These astrocytic
changes are most likely nonspecific and seem to be the
consequence of severe inflammation and microglia acti-
vation (Sharma et al., 2010). However, activated astro-
cytes can produce a large number of proinflammatory

Fig. 19.2. Macroscopic appearance of multiple sclerosis. Chronic multiple sclerosis in a 61-year-old female with a 33-year history;
section through the formalin-fixed brain (A) and the corresponding hemispheric section (B, luxol fast blue) shows multiple well-
demarcated demyelinated plaques in the periventricular white matter (arrows).
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R. HOFTBERGER AND H. LASSMANN

Fig. 19.3. Macroscopic appearance of multiple sclerosis in the brainstem. Chronic multiple sclerosis lesions (arrows) in the pons
(A) and medulla oblongata (B) of a 47-year-old female with an 18-year history. Sections through the formalin-fixed brain (A, B)
and corresponding histologic sections (C, D, luxol fast blue) show multiple well-demarcated demyelinated plaques (arrows).

Fig. 19.4. Actively demyelinating lesion. Serial sections of the edge of an actively demyelinating multiple sclerosis plaque from a
white-matter biopsy of a 22-year-old female. Periplaque white matter is seen on the right side of (A) and (B) (arrows). The plaque
on the left side shows active demyelination with numerous macrophages containing myelin basic protein-positive myelin debris
within their cytoplasm (A, rectangle enlarged upper right). Numerous CD68-positive macrophages (B) are mixed with CD3 + (C),
CD4 + (D) and CD8 + parenchymal T cells (E) and perivenous CD79a + B cells/plasma cells (F, arrow).  200.
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM 269
cytokines and chemokines and therefore these cells may hypothesized that a CNS-resident immune response
also be involved in the propagation of inflammation and might be involved (Metz et al., 2007).
tissue damage (Brosnan and Raine, 2013).
Chronic inactive lesions. In long-standing MS, the
most common lesion type is the chronic inactive demye-
Smoldering (slowly expanding) lesions. These
linated lesion. Such lesions are usually hypocellular in
lesions are mainly seen in patients with progressive
the center and may show thin myelin sheaths at the edge,
MS (Frischer et al., 2015) and show a rim of activated
representing remyelination (Fig. 19.5G). Only few mac-
microglia at the edge, while the lesion center is inactive
rophages and T cells are found, being present mainly in
(Fig. 19.5 A–D). They contain few macrophages at the
the perivascular space (Fig. 19.5 H and I). Although
edge that are digesting myelin components (Fig. 19.5B)
myelin is the primary target in MS, there is also pro-
and are accompanied by scattered T cells (Fig. 19.5
nounced axonal damage, which can lead to an average
E and F), suggesting an ongoing expansion into the sur-
axonal loss of 20–30% compared to control white matter
rounding NAWM. Slow expansion of such lesions
in newly formed lesions (van Waesberghe et al., 1999;
within a timeframe of 3 years was demonstrated in a
Kornek et al., 2000; Lovas et al., 2000) and of
recent prospective MRI study (Dal-Bianco et al.,
60–70% in chronic established lesions (Mews et al.,
2017). Acute axonal injury is prominent at the edge
1998; Bjartmar et al., 2000). The astrocytes form a dense
of these lesions. Moreover, accumulation of iron has
fibrillary gliosis.
been demonstrated in microglia at the lesion edge,
resulting in microglial dystrophy, while remyelination
Demyelinating lesions in the gray matter
is absent (Hametner et al., 2013). The driving force that
leads to a continuous expansion of the lesions is still In addition to predilection sites in the white matter, the
unclear. Since autologous stem cell transplantation cortex is especially vulnerable to demyelination. Cortical
failed to terminate the disease progression, it has been demyelination is more likely to be found in chronic

Fig. 19.5. Smoldering (slowly expanding) and inactive lesions. Serial sections of the edge of a smoldering demyelinating lesion
(A, rectangle enlarged in B; myelin basic protein (MBP)) shows a rim of activated microglia and macrophages at the edge (C,
rectangle enlarged in D; CD68). Few macrophages are digesting myelin components (B, arrow: macrophage with MPB-positive
degradation products) and are accompanied by scattered CD8 + T cells (E, rectangle enlarged in F), suggesting an ongoing expan-
sion into the surrounding normal-appearing white matter. In contrast, inactive lesions show thin myelin sheaths at the edge,
representing remyelination (G), and only contain few microglia/macrophages (H) and T cells (I) at the edge. A, C, F, G–I,
 10; B, D, F, 400.
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R. HOFTBERGER AND H. LASSMANN

Fig. 19.6. Cortical demyelination. Cortical demyelination located subpially (A, B), intracortically (C), and overlapping with the
white matter (so-called compound plaques) (D). A subpial lesion extends over several gyri and sulci and covers almost the entire
cortex (A, proteolipid protein, arrows; B, myelin basic protein (MBP), arrows). A small, demyelinated lesion is located intracor-
tically (C, MBP, arrows). A compound plaque is overlapping the cortex and the subcortical white matter (D, MBP, arrows).
B, 1.56; C, 40; D, 0.59.

disease stages (Kutzelnigg et al., 2005) and is associated
with cognitive deficites and, in some patients, with epi-
lepsy. These lesions can be located subpially or intracor-
tically, or overlap with the white matter (so-called
compound plaques) (Kidd et al., 1999), and subpial
lesions are disease-specific for MS (Moll et al., 2008;
Fischer et al., 2013). The subpial lesions often extend
over several gyri and sulci and can cover up to 70% of
the cortex in some patients (Fig. 19.6 A and B)
(Kutzelnigg et al., 2005), while intracortical lesions are
mostly small and inconspicuous (Fig. 19.6C). The com-
pound plaques affect the cortex and the underlying white
matter and are mostly more inflammatory and have more
microglial and astroglial activation compared to other
cortical lesion types (Fig. 19.6D) (Peterson et al.,
2001). Subpial cortical lesions are associated with
inflammatory infiltrates in the adjacent meninges and
are most pronounced in the invaginations of the brain
surface, most likely due to the comparatively low CSF
flow in these areas (Haider et al., 2016).
It has been hypothesized that soluble mediators are
diffusing into the cortex and induce tissue damage either
directly or indirectly through microglia activation and
oxidative stress (Howell et al., 2011; Fischer et al.,
2013). Not all patients with MS have cortical plaques;
however, accumulation of meningeal inflammation with
chronicity of the disease, aging of the patient with accu-
mulation of iron in the brain (Lassmann, 2012), and
distant lesions within the white or deep gray matter that
are in topographic relation to the cortex (Kolasinski et al.,
2012) may play a role in vulnerability.
Remyelination
Remyelination of demyelinated lesions occurs spontane-
ously but is often structurally and functionally incom-
plete. Remyelination is mediated by oligodendrocyte
precursor cells (OPC) that are present in the normal white
matter. During remyelination the OPCs are activated and
subsequently migrate to the lesion and undergo differen-
tiation into myelin-generating cells. Remyelinated fibers
are characterized by thinner myelin sheaths and may be
only encountered at the border zone of a lesion or can
also fully remyelinate a lesion, which is then called a
shadow plaque (Fig. 19.7 A–C). Some shadow plaques
may undergo new demyelination, either within or over-
lapping the previously remyelinated areas (Prineas
et al., 1993; Bramow et al., 2010). The extent of remye-
lination varies considerably between patients and seems
to be more prevalent in the early stage of the disease and
in lesions with inflammation and macrophage activity
(Foote and Blakemore, 2005). Repair capacity is also
dependent on the lesion site, with periventricular lesions
showing less extensive remyelination (Patrikios et al.,
2006). The lack of remyelination in a considerable num-
ber of patients has been attributed to a failure of OPC
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM
Fig. 19.7. Remyelinating shadow plaque. Overlap of a sharply
demarcated chronic inactive plaque centered by a small vein,
next to a remyelinated shadow plaque on the left, characterized
by thinly myelinated fibers, demonstraded in hematoxylin and
eosin (A), luxol fast blue (B), and myelin basic protein (C).
differentiation, which may be influenced by age and hor-
mones (Chang et al., 2002; Chari et al., 2003; Kotter
et al., 2011), loss of axons in the lesions (Charles et al.,
2002), and the loss of macrophages in the chronic lesion.
NEURODEGENERATION
During early and late stages of MS, axons, neurons, and
synapses can be damaged, which is commonly termed
neurodegeneration (Peterson et al., 2001; Dutta and
Trapp, 2011). Axonal loss has been suggested to be a
substrate for permanent motor disability in MS
(Tallantyre et al., 2010). Acute axonal damage is most
pronounced in the active demyelinating lesions and
can be visualized with immunohistochemistry for
271
amyloid precursor protein that reflects disturbance of fast
axonal transport in dystrophic axons (Ferguson et al.,
1997; Trapp et al., 1998; Kuhlmann et al., 2002). The
loss of myelin contributes to axonal damgage because
of the loss of trophic factors. Moreover, oxidative injury
directly damages axons. In addition, antibodies have
been identified that target glioaxonal proteins in the jux-
taparanodal area, such as anti-neurofascin155 and anti-
contactin1 (Mathey et al., 2007), that later turned out
to play an important role in a proportion of patients with
chronic inflammatory demyelinating polyneuropathy
(Ng et al., 2012). In chronic MS lesions the axons are
markedly reduced, which is considered to contribute to
a failure of remyelination (Kornek et al., 2000).
Neuronal damage may be a consequence of retrograde
neurodegeneration when axons are transected and is
morphologically associated with chromatolysis in neuro-
nal cell bodies (Haider et al., 2016). In this case, the loss
of neurons is in topographic relation to the white-matter
lesions and the loss of neurons is most pronounced in the
deep layers of the cortex and deep gray-matter nuclei
(thalamus and globus pallidus). On the other hand, neu-
ronal damage may be directly mediated by oxidative
injury. These neurons are morphologically characterized
by dendritic beading and fragmentation and accumula-
tion of oxidized phospholipids in the cytoplasm. This
pattern of damage can mainly be found in demyelinating
cortical lesions (Haider et al., 2016).
Tumefactive MS
Tumefactive demyelination is a variant of MS that is
characterized by lesions with pseudotumoral appearance
with a size often larger than 2 cm, cystic changes, or ring
enhancement on MRI, and may have a mass effect
(Enzinger et al., 2005). The lesions can be solitary or mul-
tiple and may occur at any site of the CNS, including the
spinal cord. Morphologically, they are typical active
demyelinating lesions with inflammation, numerous mac-
rophages, and bizarre reactive gliosis. It is important to
know this variant of MS because the lesions are often
biopsied or even resected and the differential diagnostic
workup may be challenging, especially in very small
biopsy specimens (Lucchinetti et al., 2008). For example,
the bizarre reactive gliosis in active MS lesions may
mimick a glioblastoma or inflammatory infiltrates may
raise the possibility of a vasculitis, infectious disease, or
even lymphoproliferative disease (Kuhlmann et al., 2008).
Acute MS
Acute MS, also referred to as Marburg´s disease, is
an acute monophasic illness that usually follows a rap-
idly progressive or stepwise deterioriating process and
leads to death within 1–6 months of clinical onset
272 €
R. HOFTBERGER AND H. LASSMANN
(Marburg, 1906). The demyelinating lesions show a
similar distribution to that in chronic MS. The plaques
appear relatively uniform within the lesion and from
one lesion to the other, which correlates with the mono-
phasic disease course. However, even within acute MS,
there is often a dissemination in time, as shown by some
variability in the lesion stages (Prineas et al., 1989).
Acute MS is nowadays extremely rare due to the avail-
ability of effective anti-inflammatory treatments and
intensive care.
Concentric sclerosis of Balo
Concentric sclerosis of Balo is a variant of MS that is
characterized by concentric rings of demyelination that
alternate with rings of relatively preserved myelin. The
disease often shows an acute onset, progresses steadily,
and may even lead to death, but can also show a benign
course, with only mild residual deficits. It is supposed
that the pathophysiologic mechanism responsible for
the formation of concentric lesions is an extensive
production of oxidative radicals leading to hypoxia-like
tissue injury and dying-back oligodendrogliopathy
(Lucchinetti et al., 2000). The zone of periplaque white
matter next to the actively demyelinating plaque reacts
with the expression of hypoxic preconditioning mole-
cules, such as HIF1alpha and Hsp-70. These molecules
have a protective effect and help to preserve a small ring
of myelin. In case of aggressive lesion progression,
however, the oxidative tissue injury extends beyond
the protected tissue ring and leads to a new ring of
demyelination (Stadelmann et al., 2005). This may
finally end up in the pattern of concentric demyelination
and preserved myelin.
NEUROMYELITIS OPTICA
Clinical and diagnostic features
NMO is a disease entity distinct from MS, which is char-
acterized by inflammatory demyelination that primarily
affects the spinal cord and the optic nerves. The disorder
is also termed Devic disease, according to one of the first
descriptions that date from 1894. NMO was long con-
sidered as a topographically restricted form of MS,
although it soon became clear that NMO patients were
different from classic MS in terms of disease course,
treatment requirements, and lesion morphology, in
particular reflected by very prominent perivascular
immunoglobulin deposition and complement activation
(Lucchinetti et al., 2002). The discovery of autoanti-
bodies to the astrocytic waterchannel AQP4 in a major-
ity of NMO patients (Lennon et al., 2004) was an
important step towards the classification of NMO as a
distinct entity and this feature is now incorporated into
the currently published diagnostic consensus criteria
for adult patients with NMO. These criteria are based on
core clinical characteristics, AQP4 antibody status, and
specific MRI requirements (Table 19.1) (Wingerchuk
et al., 2015) and allow the inclusion of spatially limited
forms (isolated optic neuritis, myelitis) or more extensive
forms of the disease (with cerebral, diencephalic, or brain-
stem lesions) into the spectrum of NMO (so-called
NMOSD).
Pathologic features of NMOSD
In classic NMO the demyelinating lesions are usually
located in the optic nerve and myelon. In the myelon
the lesions typically overlap with the gray matter and
extend over more than three vertebral segments
(Fig. 19.8 A–C). Moreover, lesions may affect the brain-
stem and exceptionally can cause demyelinating lesions
in the brain (Pittock et al., 2006; Wingerchuk et al.,
2015). Lesions in NMOSD can present with different
morphologic features (Misu et al., 2013).
The classic pattern is characterized by demyelination
and necrosis with loss of axons and astrocytes, leading to
cystic cavitation and loss of AQP4, AQP1, and glial
fibrillary acidic protein immunoreactivity. In the active
stage, inflammatory infiltrates often contain eosinophilic
granulocytes (Fig. 19.9A) next to macrophages and lym-
phocytes and deposition of IgG (Fig. 19.9B) and IgM as
well as activated complement (Fig. 19.9C) (Lucchinetti
et al., 2002). In other lesions myelin is only mildly
affected and the pathology mainly concentrates on the
astrocytes with selective loss of AQP4 (Fig. 19.9 D
and E) and/or deposition of complement, loss of perivas-
cular astrocyte processes, and accumulation of bizarre
astrocytes with beading and clumping of cell processes
(so-called clasmatodendrosis) (Fig. 19.9 F). Some
lesions with preserved myelin and loss of AQP4 may
show apoptotic oligodendroycytes and expansion of
the extracellular space or vacuolation consistent with
intramyelinic edema (Fig. 19.10 A–H).
Lesions at the floor of the fourth ventricle often show
intense inflammation and AQP4 loss, with reactive glial
fibrillary acidic protein-positive astrocytes and preserved
myelin. Whether these different morphologic patterns
represent a different lesion age or reflect variable patho-
genetic processes is presently unclear. The loss of AQP4
in active NMO lesions is in contrast to active lesions in
MS that are charaterized by upregulation of AQP4 on
reactive astrocytes. However, in chronic inactive demye-
linated MS plaques, AQP4 may sometimes be absent
(Roemer et al., 2007), which may give rise to an errone-
ous NMO diagnosis.
The deposition of complement and immunoglobulin
on perivascular astrocytic processes that show the
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM 273
Table 19.1
Diagnostic criteria of neuromyelitis optica and spectrum disorders (NMOSD) for adult patients (Wingerchuk et al., 2015)

AQP4 antibody-positive
All of the following requirements:
1. At least one core clinical featurea
2. Positive AQP4 antibodies
3. Reasonable exclusion of alternative causes
AQP4 antibody-negative or unknown
All of the following requirements:
1. At least two core clinical features; one of them has to be optic neuritis, acute myelitis with LETM, or area postrema syndromea
2. Dissemination in space
3. Fulfillment of additional MRI requirementsb
4. Negative test for AQP4 antibodies (using the best available detection method) or testing unavailable
5. Reasonable exclusion of alternative causes
a
Core clinical features: (1) optic neuritis; (2) acute myelitis; (3) area postrema syndrome (hiccups, nausea, and/or vomiting); (4) acute brainstem
syndrome; (5) narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; (6) symptomatic cerebral
syndrome with NMOSD-typical brain lesions.
b
Additional magnetic resonance imaging (MRI) requirements for AQP4 antibody-negative NMOSD: (1) optic neuritis with either normal/nonspecific
MRI or T2-hyperintense or T1-weighted gadolinium enhancing lesions extending over >1/2 optic nerve length or involving optic chiasm; (2) acute
myelitis with intramedullary MRI lesion extending over three or more vertebral segments (longitudinal extensive transverse myelitis: LETM); (3) area
postrema syndrome: dorsal medulla/area postrema lesions in MRI; (4) acute brainstem syndrome: periependymal brainstem lesions in MRI.
AQP-4, aquaporin-4.

Fig. 19.8. Spinal cord lesion in neuromyelitis optica. Destructive demyelinating lesion in the spinal cord (A, myelin basic protein)
shows loss of astrocytes (B, aquaporin-4; C, aquaporin-1) and overlaps with the gray matter.  1.1.

hightest concentration of AQP4 is consistent with the
current concept that humoral autoimmunity to AQP4
mediates the disease and distinguishes it from MS. How-
ever, it is still unclear why NMO lesions have a particular
predilection for the optic nerves and the myelon.
ACUTE DISSEMINATED
ENCEPHALOMYELITIS AND RELATED
DISORDERS
Clinical and diagnostic features
ADEM is an acute monophasic inflammatory demyelin-
ating disease of the CNS. Although it can occur at any
age, it mainly affects children and young adults
(Wingerchuk, 2006). The disease may be preceded by
an infectious disease or, less frequently, by vaccination
(Wingerchuk, 2003; Karussis and Petrou, 2014), and sea-
sonal accumulation of the disease in winter and spring
months has been reported (Dale et al., 2000; Leake
et al., 2004). Clinical diagnostic criteria are currently
only available for the pediatric age group and include
neurologic symptoms and specific MRI features and
are summarized in Table 19.2 (Krupp et al., 2013).
A subgroup of patients with ADEM has antibodies to a
conformational epitope of MOG in serum. These anti-
bodies are particularly prevalent in children and can be
used as biomarkers. Relapsing variants of ADEM are
multiphasic disseminated encephalomyelitis (MDEM)
and ADEM followed by episodes of optic neuritis
(ADEMON). Recurrences in MDEM can either affect
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R. HOFTBERGER AND H. LASSMANN

Fig. 19.9. Active stage of neuromyelitis optica (NMO) lesion. An active NMO lesion shows inflammatory infiltrates with eosin-
ophils (A, hematoxylin and eosin) next to macrophages and lymphocytes, deposition of immunoglobulin G (B, IgG), and C9 neoan-
tigen (C, arrows). Some lesions show selective loss of aquaporin-4 (D, asterisk marks lesion) while aquaporin-1 is well preserved
(E) and there is accumulation of bizarre astrocytes with beading and clumping of cell processes (clasmatodendrosis) (F, glial fibril-
lary acidic protein). A, B, F, 600; C, 200; D, E, 100.

Fig. 19.10. Vacuolated lesions in neuromyelitis optica (NMO). A vacuolated lesion in NMO is characterized by expansion of the
extracellular space and shows some apoptotic nuclei (A, B, hematoxylin and eosin, arrow: apoptotic cell). The myelin is relatively
well preserved with only few demyelinating macrophages (C, D, luxol fast blue (LFB); arrow: macrophage with LFB-positive
degradation products; E, F, myelin basic protein; arrowhead: apoptotic cell), in contrast, astrocytes are lost (G, H, glial fibrillary
acid protein). B, D, F, H:  250.
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM
Table 19.2
Diagnostic criteria of acute dissemimated
encephalomyelitis (Krupp et al., 2013)
All of the following requirements:
1. A first multifocal, clinical central nervous system event of
presumed inflammatory demyelinating cause
2. Encephalopathy that cannot be explained by fever
3. Abnormal brain magnetic resonance imaging (MRI):
a. Diffuse, poorly limited, large (>1–2 cm) lesions that
predominantly involve the cerebral white matter
b. T1 hypointense lesions in the white matter are rare
c. Deep gray-matter lesions (e.g., thalamus or basal ganglia)
can be present
4. No new clinical and MRI findings after 3 months of
symptom onset
275
different brain loci or occur at the same site in each
relapse (Cohen et al., 2001) and may reflect either a spe-
cific susceptibility or an antigenic modification in the
affected brain areas after a local infection. The rate of
recurrent variants of ADEM has been reported in up to
one-third of patients (Anlar et al., 2003) and the clinical
differentiation to MS in these patients is particularly
challenging.
Pathologic features of ADEM
The characteristic lesions of ADEM consist of small
veins that are surrounded by foamy macrophages with
or without T-cell-dominated inflammatory infiltrates
(Fig. 19.11A). The adjacent parenchyma shows active
demyelination with macrophages that contain luxol fast

Fig. 19.11. Acute disseminated encephalomyelitis (ADEM). Lesions in ADEM are characterized by small perivenous demyelin-
ating areas (A, luxol fast blue (LFB)), with numerous macrophages containing LFB-positive degradation products (B, LFB; C,
CD68). A, C,  100; B,  600.
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R. HOFTBERGER AND H. LASSMANN
blue-positive myelin components and neutral lipids
(Fig. 19.11 B and C). The demyelination is restricted
to the perivascular region and axons are relatively pre-
served but also show features of acute injury (Young
et al., 2010). The vessel walls may sometimes show fibri-
nous exudates and the adjacent parenchyma may
undergo necrosis, indicating an overlap of ADEM and
acute hemorrhagic leukoencephalitis. In typical ADEM
the demyelinating perivenous lesions appear to be of
the same histologic age.
The lesions can be located throughout the CNS or lim-
ited to a single region. Although they are most numerous
in white matter, the lesions can also involve the cortex,
thalamus, and basal ganglia (Tenembaum et al., 2002).
Involvment of spinal cord, brainstem, and cerebellum
is also common. Although the occurrence of nonconflu-
ent perivenous lesions is characteristic of ADEM and dis-
tinguishes them from the large confluent perivenous
lesions of MS (Young et al., 2010), there are occasional
patients in whom the clincal history is suggestive of
ADEM but pathology overlaps with MS. Whether this
represents a different pathogenic process (e.g., anti-
MOG antibody-associated ADEM) or patients who have
a higher likelihood to convert to MS remains to be
clarified.
Immunopathogenesis
ADEM is usually preceded by infectious diseseases or,
less frequently, by vaccination. It has been shown that
some myelin peptides resemble antigens of viruses such
as influenza virus, Epstein–Barr virus, human
herpesvirus-6, or coronavirus (Giovannoni et al.,
2006). Thus it has been postulated that the infectious
agents may stimulate T cells that subsequently attack
similar or even identical CNS epitopes. Alternatively, a
direct infection of the brain parenchyma exposes CNS
antigens to the immune system, affects the BBB, and
triggers the autoimmune disease (Steiner and Kennedy,
2015). Finally it has been shown that certain MHC class
II alleles are associated with the condition (Woody
et al., 1989).
MOG ANTIBODY-ASSOCIATED
DEMYELINATING
ENCEPHALOMYELITIS
Clinical and diagnostic features
MOG is a minor myelin protein and expressed on the sur-
face of CNS myelin sheaths (Delarasse et al., 2006).
MOG belongs to the immunoglobulin superfamily and
is believed to play a role as surface receptor or cell adhe-
sion molecule (Martini and Schachner, 1986). Antibodies
of the IgG1 subclass against MOG have been found in
serum of patients with inflammatory demyelination,
including a subgroup of patients with ADEM, ADEMON,
seronegative (AQP4-negative) NMOSD, monophasic, or
recurrent isolated optic neuritis and transverse myelitis,
MDEM, N-methyl-D-aspartate receptor encephalitis over-
lapping with demyelinating syndromes, and, rarely, MS
(Di Pauli et al., 2011; Mader et al., 2011; Probstel et al.,
2011; Kitley et al., 2012, 2014; Rostasy et al., 2012,
2013; Huppke et al., 2013; Sato et al., 2014; Titulaer
et al., 2014; Hoftberger et al., 2015b; Baumann et al.,
2016; Jarius et al., 2016b).
The detection of MOG antibodies in serum and CSF
of patients depends on the use of appropriate test
methods that conserve the conformation of the protein,
such as in live cell-based assays transfected with the
full-length human MOG (Mader et al., 2011). MOG
antibodies that are tested with these methods serve
as sensitive and specific diagnostic markers. MOG
antibodies are particularly prevalent among pediatric
ADEM patients, where they occur in up to 50%.
Children with MOG antibody-positive ADEM show a
characteristic MRI pattern with large, hazy, bilateral
lesions and wide anatomic involvement, including the
myelon with longitudinal extensive transverse myelitis
(Baumann et al., 2015). While MOG antibodies are usu-
ally transient in patients with ADEM and associated
with a monophasic disease course (Probstel et al.,
2011), they often persist in patients with optic neuritis
and myelitis and may be associated with a relapsing
course and severe disability in a substantial number of
patients (Jarius et al., 2016b). Demyelinating diseases
associated with MOG antibodies are often difficult to
categorize and some patients meet the diagnostic criteria
of AQP4 antibody-positive NMOSD, while others can
be classified as MS. Since it is assumed that all MOG
antibody-positive patients have the same underlying
immunopathogenesis that requires the same therapy, it
has been suggested that it may be useful to subsume
them as a distinct disease entity. It is important to note
that the therapeutic response in MOG antibody-positive
patients is similar to that in NMO, but different from that
in MS patients (Jarius et al., 2016b).
Pathologic features of MOG antibody-
associated demyelinating encephalomyelitis
Neuropathology of MOG-antibody associated demye-
lination has been described in a few patients with relaps-
ing remitting MS, atypical demyelination, clinically
isolated syndrome, ADEM, and NMOSD (Table 19.3)
(Konig et al., 2008; Di Pauli et al., 2015; Spadaro
et al., 2015; Jarius et al., 2016a; Wang et al., 2016). Irre-
spective of the clinical nosology, all cases showed demy-
elinating features of MS pattern 2, with well-demarcated
 INFLAMMATORY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM 277
Table 19.3
Neuropathological reports of myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination

Sex,
age
Demyelinating disease (years) n Reference Neuropathology

Relapsing remitting MS F, 49 1 Konig et al., MS pattern II; oligodendrocytes preserved (CNPase +;

2008 MOG n.d.)
Recurrent myelitis with F, 66 1 Spadaro et al., MS pattern II; oligodendrocytes preserved (CNPase +;
brainstem involvement 2015 MOG–)
ADEM/acute MS; seropositive M, 71 1 Di Pauli et al., MS-pattern II; oligodendrocytes preserved (CNPase+,
for MOG and AQP4 2011 MOG–)
Clinically isolated syndrome F, 63 1 Jarius et al., MS pattern II; oligodendrocytes preserved (CNPase+,
2016a MOG +)
NMOSD F, 67 1 Wang et al., Pattern classification not done; well-demarcated
2016 demyelinating lesion with preserved astrocytes and
axons
ADEM M, 49 2 K€ortvelyessy Case 1: overlapping features of MS pattern II and III
intrathecal MOG-antibody M, 34 et al., 2017 (early MAG loss, apoptotic oligodendrocytes in
synthesis addition to complement deposition)
Case 2: MS pattern III; oligodendrocytes preserved
(CNPase+, MOG +)

ADEM, acute dissemimated encephalomyelitis; AQP4, aquaporin-4; MAG, myelin-associated glycoprotein; MS, multiple sclerosis; NMOSD,
neuromyelitis optica and spectrum disorders.

Fig. 19.12. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating encephalomyelitis. A demyelinating
lesion associated with MOG antibodies is well demarcated (A, luxol fast blue) and shows relatively well-preserved (B, CNPase;
C, MOG) oligodendrocytes and deposition of C9 neoantigen (D, arrows).  200.

confluent plaques with loss of myelin (Fig. 19.12A), rel- parenchymal T cells and some perivascular B cells.
ative preservation of axons, numerous macrophages, and Lesions were characterized by relatively well-preserved,
well-preserved astrocytes. The inflammaotry infiltrates partly MOG-negative oligodendrocytes, most likely com-
were predominantely composed of perivascular and patible with preoligodendrocytes (Fig. 19.12 B and C)
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R. HOFTBERGER AND H. LASSMANN
and deposition of terminal complement complex C9neo,
indicating a complement-mediated demyelination
(Fig. 19.12D). Whether MOG antibodies have a patho-
genetic role in disease formation is unclear. Different
EAE animal models indicate that MOG antibodies can
induce demyelinatin in vitro and in vivo (Linington
et al., 1988; Zhou et al., 2006). However, it cannot be
excluded that in humans they represent a bystander phe-
nomenon, secondary immune reaction, or even may
mediate a beneficial effect (Reindl et al., 2013).
HUMAN EXPERIMENTAL AUTOIMMUNE
ENCEPHALOMYELITIS
Human EAE is produced by an unintentional inoculation
or vaccination of CNS tissue. Cases have been described in
workers of a slaughterhouse, who were repeatedly exposed
to an aerosol of brain tissue and developed polyradiculo-
neuropathy or an ADEM-like condition (Lachance et al.,
2010). Moreover, human EAE occurred in association
with rabies vaccination using vaccines which contain brain
tissue (Semple-type rabies vaccine) (Stuart and Krikorian,
1928; Kulkarni et al., 2004) or after treatment with fresh
brain cells or lyophilized brain tissue, which was used in
alternative medicine (Jellinger and Seitelberger, 1958).
Most patients who survived showed a monophasic, self-
limiting disease without evidence of relapse and were rem-
iniscent of clinical and pathologic features of ADEM or
inflammatory demyelinating polyneuropathy (Lachance
et al., 2010). A rare subset of patients, however, showed
a pathologic picture closely resembling acute MS
(Uchimura and Shiraki, 1957; Jellinger and Seitelberger,
1958). A detailed immunopathologic analysis of one of
these cases revealed close similarities regarding inflamma-
tion, demyelination, and neurodegneration to those in
acute MS, while essential pathologic features differed from
those seen in EAE animal models in primates or rodents
(Hoftberger et al., 2015a). However, none of these patients
developed chronic disease, when the active sensitization
was ceased and the patient survived the acute or subacute
disease episode.
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